1. Field of Invention
The present invention improves the safety of the use of sodium nitroprusside in the clinical setting. Specifically, this invention suggests that alpha-ketoglutaric acid or alpha-ketoglutaric acid and sodium thiosulfate antagonize sodium nitroprusside's toxic effects. The antagonism of sodium nitroprusside's toxic effects by alpha-ketoglutaric acid or alpha-ketoglutaric acid and sodium thiosulfate is effective as a prophylactic treatment administered prior to exposure to sodium nitroprusside as a simultaneous treatment administered with exposure to sodium nitroprusside, and as an antidotal treatment administered following exposure to sodium nitroprusside. Alpha-ketoglutaric acid or alpha-ketoglutaric acid and sodium thiosulfate provide better antagonism of sodium nitroprusside's toxic effects than other regimens utilized in the past. The presence of alpha-ketoglutaric acid or sodium thiosulfate does not prevent the hypotension induced by sodium nitroprusside. This hypotension is the desirable effect of sodium nitroprusside. Alpha-ketoglutaric acid and sodium thiosulfate are without toxicological properties.
2. Prior Art
In the metabolism of nitroprusside (or sodium nitroprusside or other salts of nitroprusside) in a mammalian system cyanide is produced and released in the body. Thus, the primary toxicity of sodium nitroprusside is that of cyanide. Presently an individual exposed to a toxicological dose of sodium nitroprusside is administered sodium thiosulfate. Sodium thiosulfate protects against sodium nitroprusside's toxic effects indirectly by antagonizing the toxic effects of the cyanide released from the sodium nitroprusside. Cyanide is detoxified by an enzyme, rhodanese, which primarily resides in the liver. The substrate for rhodanese, sulpbate, is the limiting factor in protection against sodium nitroprusside's toxic effects. Administration of sodium thiosulfate provides additional substrate for rhodanese and thus enhances the body's ability to detoxify cyanide. Sodium thiosulfate must circulate to the liver before it can provide any assistance in cyanide detoxification. Consequently, there is a delay from the time of sodium thiosulfate administration to time of affecting the detoxification of cyanide.
Direct binding of cyanide by other chemicals have been proposed. Cobalt edetate is a chemical that binds cyanide but it has toxic effects of its own, e.g. atrial fibrillation, gastrointestinal hemmorrhage and anaphylactoid reactions. Another chemical that binds cyanide is hydroxocobalamin. Since one molecule of hydroxocobalamin binds one molecule of cyanide, large quantities would be needed to bind all the cyanide released from sodium nitroprusside. Experimental data suggest that the weight of hydroxocobalamin used would have to be 250 times the weight of sodium nitroprusside.
Listed below are selected articles known to the inventors on sodium nitroprusside's toxic effects and antagonism of sodium nitroprusside's toxic effects.
Arnold, W. P., Longnecker, D. E., and Epstein, R. M. (1984). Photodegradation of sodium nitroprusside: Biologic activity and cyanide release. Anesthesiology, 61: 254. PA0 Bulter, A. R., Glidewell, C., and Bisset, W. I. K. (1982). Sodium nitroprusside and cyanide release. Br. J. Anaesth. 54: 792. PA0 Davies, D. W., Kadar, D., Steward, D. J., and Munro, I. R. (1975). A sudden death associated with the use of sodium nitroprusside for induction of hypotension during anaesthesia. Canad. Anaesth. Soc. J. 22: 547. PA0 Graham, G. G., and Rigg, D. (1983). Nitroprusside infusions. Br J. Anaesth. 55: 919. PA0 Isom, G. E., Burrows, G. E., and Way, J. L. (1982). Effect of oxygen on the antagonism of cyanide intoxication-cytochrome oxidase, in vivo. Toxicol. Appl. Pharmacol. 65: 250. PA0 Jack, R. D. (1974). Toxicity of sodium nitroprusside. Br. J. Anaesth. 46: 952. PA0 Keilin, D. (1929). Cytochrome and respiratory enzymes. Proc. Roy. Soc. Ser. B. 104: 206. PA0 Merrifield, A. J., and Blundell, M. D. (1974). Toxicity of sodium nitroprusside. Br. J. Anaesth. 46: 324. PA0 Moore, S. J., Norris, J. C., Ho, I. K., and Hume, A. S. (1986). The efficacy of .alpha.-ketoglutaric acid in the antagonism of cyanide intoxication. Tox. Appl. Pharmacol. 82: 40. PA0 Norris, J. C., and Hume, A. S. (1985). Antagonism of sodium nitroprusside-induced lethality by .alpha.-ketoglutaric acid. Federation Proceedings 44: 719. PA0 Norris, J. C., and Hume, A. S. (1986). In vivo release of cyanide from sodium nitroprusside. Br. J. Anaesth. (In Press). PA0 Smith, F. M., Aitken, D. M., West, D. W., Peterson, E. W., and Posnanski, W. D. (1977). Cyanide toxicity associated with sodium nitroprusside use. Ann. R. Coll. Phys. Surg. Can. 10: 83. PA0 Smith, R. P., Kruszyna, H., and Kruszyna, R. (1982). Cyanide release from nitroprusside. Br. J. Anaesth. 54: 1145. PA0 Vesey, C. J., Cole, P. V., Linnell, J. C., and Wilson, J. (1974). Some metabolic effects of sodium nitroprusside in man. Br. Med. J. 2: 140. PA0 Vesey, C. J., Cole, P., and Simpson, P. (1976). Changes in cyanide concentrations induced by sodium nitroprusside. Br. J. Anaesth. 48: 268. PA0 Vesey, C. J., and Batistoni, G. A. (1977). The determination and stability of sodium nitroprusside in aqueous solution. J. Clin. Pharm. 2: 105. PA0 Vesey, C. J., Cole, P., and Simpson, P. (1982). Sodium nitroprusside and cyanide release. Br. J. Anaesth. 54: 791.
3. Summary Discussion of the Invention
It is an object of the present invention to provide an antagonist to sodium nitroprusside's toxic effects which is fast acting and is free from its own toxic properties.
It is another object of the present invention to provide an antagonist to sodium nitroprusside's toxic effects which is effective as a preventive measure administered prior to and simultaneous with exposure to sodium nitroprusside and as a remedial measure employed after exposure to sodium nitroprusside.
It is still another object of the present invention to provide an antagonist to sodium nitroprusside's toxic effects which may be employed singularly or in concert with presently known antagonists to sodium nitroprusside's toxic effects, e.g., sodium thiosulfate, for an additive effect.